DEVELOPMENT OF THE ENDOCRINE

SYSTEMProf. Dr. Olcay Evliyaoğlu

 

Steroid hormones:

are not stored

rate of synthesis = rate of secretion

Adrenal, gonadal steroids:

Synthesis is controlled by trophic hormones.

Stimulating hormone -------> receptor --------> activation of adenylate cyclase ------> cAMP increases

McCune Albright Syndrome: Activating mutation in the alpha subunit of G protein.

Testotoxicosis: Activating mutation of LH receptor ( transmembrane domain - interaction with G protein.)

Disorders of hormone resistance

Insulin resistance

Testicular feminization

Certain types of dwarfism

Diabeted insipidus (nephrogenic)

Pseudohypoparathyroidism

Hormone ↑ --> receptor number decreases

“down regulation” or “desensitization”

obesity - insulin

precocious puberty - GnRH analogues

Hormone ↑ --> receptor number increases

“up regulation”

estrogen - FSH ↑ ---> LH receptors increase

Distinguishing characteristic of endocrine systems: feedback control & hormone production.

The paradigm for feedback control is the interaction of the pituitary gland with the thyroid, adrenals and gonads.

Hormones produced in peripheral endocrine organs feedback on the hypothalamic-pituitary system ------> regulate the production of the trophic hormones that control peripheral endocrine glands.

Negative Feedback

Metabolite

Cortisol --> ACTH/ CRH

Thyroid hormones --> TSH /TRH

Short Feedback

TSH --> TRH

ACTH --> CRH

Positive Feedback

Hypophysogonadal (only example) : Estrogen --> LH, FSH

 

Adrenal gland develpmentEmbryology

Mesoderm........adrenal cortex

Ectoderm.........adrenal medulla

5-6 wk fetal adrenal cortexOuter definitive zone (glucokortikoids and

mineralocorticoids) Inner fetal zone (androgenic precursors)

At birth AG is 0,5 % of total BW

Glomerulosa 15 %

Fasiculata 75 %

Reticularis 10 %

Fetal zone disappears around 1 years of age

Glomerularis and fasiculata development is completed in 3 years.

Reticularis development is completed in 15 years

Fetal cortisol --> cortisone

(Midgestation: cortisone (x4-5 cortisol))Cortisone: relatively inactive glucocorticoid; it

protects the anabolic milieu of the fetus: cortisol can retard placental and fetal growth.

As term approaches; liver, lung express 11-beta hydroxy steroid dehydrogenase I activity:

cortisone --> cortisolCortisol: an important stimulus for preparing the

fetus for extrauterine survival.

Development of pituitary gland

Growth hormone The most produced hormone in the pituitary.

Single chain alpha-helical nonglukolized polypeptide.

Consists of 191 aminoacids and two intramolecular disulfide bounding.

22kDa molecüler weight 75%

20kDa 10-25%

N-asetile ve desamine forms veya oligomers

GH

GH-BHBP

Extracellular part of GH rec

Growth hormoneEncoded by GH-1 gene.

Locolized on 17q 22-24 chromosome.

GH secretionUnder control of 2 hypothalamic hormones

Growth hormone releasing hormone(GHRH)Somatotropin release-inhibiting factor (SRIF,

somatostatin)

GHRHProtein with 44 aminoacids

Vazoactive intestinal polypeptide/ glukagon family

GH secretion

Human growth hormone (hGH)

Nonpulsatile GH secretion in infants.

During childhood 24 hour integrated GH secretion increase progressively.

In puberty GH secretion amplitude increase to peak levels ( effect of gonadal steroids on GHRH).

GH secretion decrease with age but secreted life long.

GH-releasing peptides (GHRP)or secretagogues (GHS)

Ligands that increase GH produced by humans

Do not use GHRH or SRIF receptors

GHS-R G-protein associated rec

protein kinase C

hypothalamus, pituitary somatotrophs

Ghrelin Endogen ligand for GHS-R. Increase GH secretion in rats (intracellular Ca

increase).Physiologic mediator of nutrition

GH effect

Bound to GH-binding protein (GHBP) (at least 50 %)

GHBP, is the extra cellular component of GH-R

GH-R member of cytokine rec family

620 aa protein

On plasma membrane.Extracellular part is transport proteinSingle transmembrans helix Intracellular part

GH

IGF’s (somatomedins)Similliar to proinsulineEffect on extrauterine growth via IGF-1ile (70aa

polypeptide)

Disorders associated with low IGF-1 levels

GH deficiency

Hypothyroidism

Malnutrition

Chronic diseases

Fetal IGF-1 is correlated with gestastional age

Newborn IGF-1 levels are 30-50 % of adult values

Increase through out childhood and reach adult levels in puberty

Gonadal steroids increase IGF-1 production.

In puberty levels are 2-3 fold higher than adult values

Increase osteoblastic activity and collagen synthesis stimulate long bone growth

IGF’ s are bound to IGF binding proteins (IGFBP)t ½Transport to target tissue. Modulate the relation with IGF rec6 different IGFBP are cloned IGFBP-3, 90 % related to GH

IGF-1 recStructure resembles insulin rec (2 alpha,2beta

subunits)

GH increaseGHRH

Arginin,leucine

Alpha adrenergic agonists (alpha 2 adrenergic)

Beta adrenergic antagonists

Dopamine, acetylcholine

Hypoglycemia

Sleeping

Exercise

GH decreaseHypergylcemia

Obesity

İncrease in free FA

Glucocortikoid excess

Hypothyroidism

Incresed adrenergic tonus

Psychosocial deprivition

Is derived from primitive pharynx-precursor of T4 producing cellsAnd fourth pharengeal pouch-precursor of calcitonin(C) cells

For development and descent of thyroid several transcription factors such asTITF1/NKX2, FOXE1 and PAX 8 are needed to work on time and coordinated

Thyroid gland development

EmbryogenesisAfter 1st month it is visable.

At ıntrauterin 8 wk Tg synthesis begins shows thyroid activity

10. wk iodine trapping

12. wk colloid formation begins and withTSH sec from pituitary T4 synthesis begins

This synthesis increase progresively with hypothalamic maturation after 18 wk of gestation

Tiroid kolloidi

tiroglobulin

Proteinsentezi

Çekirdek DNA/RNA sentezi

Damar

G proteini

Thyroid hormone biosynthesis

Thyroid hormone synthesis

Uptake I uptake actively with Na-iodine pump

Thyroid hormone synthesis

Organification İyodine + thyroglobulin

MIT

DIT

Thyroid hormone synthesis

Conjugation MIT + DIT T3DIT +DIT T4

Thyroid peroksidase(TPO)

TİROKSİN (T4)TİROKSİN (T4)

I

HO

I

1’

2’3’

4’

5’ 6’

O

I

I

1

23

4

5 6

CH2 CH

COOH

NH2

(fenol halkası) (tirozil halkası)

I

R O

I

I

R

I

R O

I

I

R

5’ - monodeyidinasyon 5 - monodeyidinasyonTip I-II monodeyiodinaz

Tip III monodeyiodinaz

T3T3 rT3rT3

Serum thyroid hormone concentrations

TT3 TBGTBGTBGTBGTT4TT4TT4TT4 rT3/T4rT3/T4rT3/T4rT3/T4

Effects of thyroid hormones Growth

O2 usage

Heat production

Nerve functions

Lipids

Proteins

Nucleic acids

Vitamins

Inorganic ions

Other hormones

Effect metabolismEffect metabolism

Actions of thyroid hormones

Regulation of thyroid hormones

Regulation of thyroid hormones

CAMP Iodine uptake

İodothyrosine synthesis

Tg synthesis

Glucose oxidation

Colloid pinositosis

Hormone secretion

Thyroid growth

ATP

Adenilate cyclaseTSH

G Protein

Regulation of thyroid hormones

Iodine intakeIodine intake

Physiologic limits

Thyroid membrane iyodine uptake

Pharmachologic doses

TPO activity

Iodine organification (Wolf Chaikoff effect)

TSH induced CAMP stimulation inhibitted

• Tg synthesis• Hormone secretion• Thyroid growth

-- --

Iodine needs in different times of age

Age and stages of lifeDaily idoine

recommendation(g)

6 < 30

6-12 months 40

1< years in iodine deficient regions

90

1-10 years 60-100Adoles and adults 100

Pregnant and lactating women 150

İYOT KLİRENSİ

dolaşım

I2I2

II

%20

%80Pasif reabsorbsiyon

İdrarla iyot atılımı

GFR++

II

ATPaz bağımlı Na-I simporter

TSH (+)Follikül hücresi

Daily iodine excretion gives intakeDaily iodine excretion gives intake

Iodine induced hyperthyoridism(Jodbasedow effect)

Iodine induced hyperthyoridism(Jodbasedow effect)

Nodular thyroid disease with otonomy and with out antibodies

Diffuse goitre with thyroid stimulating antibodies

Jodbasedow effect only in thyroids independent from TSH

Iodine deficiencyIodine deficiency

Iodine deficiency disorders (IDD) global heath problem

World’s most common endocrine disorder

Most frequent reseason for goitre and hypothyroidism

IDDIDD

Goitre

Hypothyroxinemia

Neurodevelopmental disorders

Cretinism

Decreased fertility

Still birth

Increased perinatal mortality

IDD indicatorsIDD indicators

Decreased urinary iodine concentration

Increased serum hTg concentration

Increased newborn and cord blood TSH concentration

Thyroid disease risk Thyroid disease risk

There is a U type relation between Iodine intake

and thyroid disease